The Kinases MEKK2 and MEKK3 Regulate Transforming Growth Factor-β-Mediated Helper T Cell Differentiation

被引：56

作者：

Chang, Xing ^{[1
,2
]}

Liu, Fang ^{[4
,5
]}

Wang, Xiaofang ^{[1
,2
]}

Lin, Aiping ^{[3
]}

Zhao, Hongyu ^{[3
]}

Su, Bing ^{[1
,2
]}

机构：

[1] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06519 USA

[2] Yale Univ, Sch Med, Program Vasc Biol & Therapeut, New Haven, CT 06519 USA

[3] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06519 USA

[4] Rutgers State Univ, Ernest Mario Sch Pharm, Susan Lehman Cullman Lab Canc Res, Piscataway, NJ 08854 USA

[5] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA

来源：

IMMUNITY | 2011年 / 34卷 / 02期

关键词：

TOLL-LIKE RECEPTOR; TGF-BETA; SMAD3; PHOSPHORYLATION; ACTIVATION; PATHWAYS; MICE; JNK; IDENTIFICATION; GENERATION;

D O I：

10.1016/j.immuni.2011.01.017

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Mitogen-activated protein kinases (MAPKs) are key mediators of the T cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are unclear. Here we showed that the MAPK kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3) negatively regulated transforming growth factor-beta(TGF-beta)-mediated Th cell differentiation. Map3k2(-/-)Map3k3(Lck-Cre/-) mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2(-/-)Map3k3(Lck-Cre/-) naive CD4(+) T cells' differentiation into Treg and Th17 cells with a higher frequency than wild-type (WT) cells after TGF-beta stimulation in vitro. In addition, Map3k2(-/-)Map3k3(Lck-Cre/-) mice developed more severe experimental autoimmune encephalomyelitis. Map3k2(-/-)Map3k3(Lck-Cre/-) T cells exhibited impaired phosphorylation of SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-beta responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-beta signaling pathways is important in regulating Th cell differentiation.

引用

页码：201 / 212

页数：12

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